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Acyline: the First Study in Humans of a Potent, New Gonadotropin-Releasing Hormone Antagonist

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Acyline: the First Study in Humans of a Potent, New Gonadotropin-Releasing Hormone Antagonist 0013-7227/02/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 87(7):3215–3220 Printed in U.S.A. Copyright © 2002 by The Endocrine Society Acyline: The First Study in Humans of a Potent, New Gonadotropin-Releasing Hormone Antagonist KAREN L. HERBST, BRADLEY D. ANAWALT, JOHN K. AMORY, AND WILLIAM J. BREMNER Department of Medicine, University of Washington (K.L.H., B.D.A., J.K.A., W.J.B.) and Medical Service, Department of Veteran Affairs, Puget Sound Health Care System (B.D.A.), Seattle, Washington 98195 Acyline is a novel GnRH antagonist found in animal studies to maintaining suppression for over 48 h. Serum acyline levels -be a potent suppressor of circulating gonadotropin and tes- peaked at1hat18.9 ؎ 0.9 ng/ml, remained significantly ele tosterone (T) levels. We conducted the first study of acyline vated above background 7 d after injection, and returned to administration to humans. Eight healthy, eugonadal young background levels by 14–17 d after injection. Side-effects at men were administered a series of acyline injections (0, 2.5, the site of injection were limited to infrequent blush and pru- 7.5, 25, and 75 ␮g/kg), each injection separated by at least 10 d. ritus that resolved within 90 min of injection. Higher doses of Serum FSH, LH, and T levels were measured for 7 d after acyline might be effective as depot injections for long-lasting injections. Acyline suppressed FSH, LH, and T levels in a dose- gonadotropin suppression in hormone-dependent diseases dependent fashion. Maximal suppression occurred after in- and for use in male hormonal contraception regimens. (J Clin (jection of 75 ␮g/kg acyline, which suppressed FSH to 46.9 ؎ Endocrinol Metab 87: 3215–3220, 2002 ,LH to 12.4 ؎ 2.2%, and T to 13.4 ؎ 1.4% of baseline levels ,2.5% nRH IS A hypothalamic peptide that stimulates the Materials and Methods G release of FSH and LH by the pituitary. GnRH an- Acyline tagonists are peptide analogs of GnRH that competitively Acyline was originally synthesized by Jean Rivier at The Salk Institute inhibit the action of GnRH at pituitary receptor sites (1). (9) and is being distributed by the NICHHD. Acyline is prepared as a They produce immediate and sustained declines in go- lyophilized powder at a concentration of 4.4 mg/vial and is stored at nadotropin and sex steroid levels and therefore have po- Ϫ20 C. In this study the acyline powder was suspended in 2.2 ml tential as treatment for hormone-dependent conditions bacteriostatic water and used within1hofreconstitution. There was no evidence of gel formation after reconstitution in water. All placebo and as contraceptive agents. Although previously studied injections consisted of bacteriostatic water equal to the smallest volume antagonists have effectively suppressed circulating go- of acyline injected into each subject (0.08–1.3 ml). In comparison, the nadotropin levels, most have histamine-releasing local ef- largest volume of acyline injected ranged from 2.28–3.67 ml for the 75 fects, including pruritic rashes, and have short half-lives ␮g/kg dose. Serum levels of acyline were measured in a subset of ␮ that require daily injection (2, 3). Some newer antagonists subjects after injection of 75 g/kg acyline by RIA using a specific antiserum and a proprietary peptide, with authentic peptide standard are not generally available for research (4–6). GnRH ago- (Woods Assay, Inc., Portland, OR) as described previously (10). The nists also suppress the gonadal axis, but can cause an sensitivity of the assay for acyline was 0.35 ng/ml. initial flare in circulating gonadotropin and testosterone (T) levels that can last for days to weeks (5). In addition, Subjects depot injections of GnRH agonists may result in small Nine men, aged 20–39 yr, were recruited by posted flyers on local surges in circulating gonadotropin and T levels over time college campus bulletin boards. All subjects were healthy, eugonadal after the initial flare (7). Efforts have therefore con- men with normal baseline physical examinations and medical histories, tinued to develop an effective, safe, and convenient GnRH including testicular size by Prader orchidometer and prostate size by antagonist. digital rectal exam, serum chemistries, complete blood count, and hor- Acyline is a GnRH antagonist that has not been studied mone levels. Subjects who smoked or had an alcohol intake greater than 7 ounces weekly, prescription medication use, or involvement in a male previously in humans. It was found in animal studies to be contraceptive study within the last 6 months were excluded from the at least 4 times more effective at suppression and mainte- study. Eight subjects completed the study; one subject withdrew from nance of suppression of gonadotropins and T than previous the study for personal reasons. All subjects were given a test dose (0.1 GnRH antagonists (8) (Contraceptive and Reproductive ml of a 2.2 mg/ml solution) of acyline intradermally during the screen- ing period to assess allergic reactions. Subjects had minimal or no re- Health Branch, Center for Population Research, NICHD, un- actions to the test dose. As an additional safety precaution, all subjects published data). In adult male rhesus monkeys, acyline was were admitted to the Clinical Research Center at University of Wash- more potent than azaline B, Nal-Glu, and lystide. No signif- ington for 24 h after each acyline injection. Each admission was sepa- icant adverse effects were observed in these animal studies. rated by at least 10 d. During each admission blood was drawn 30 min before and immediately before the injection of acyline. Acyline or pla- We tested the hypothesis that acyline would effectively and cebo was administered by sc injection in the abdomen between 0700– safely suppress circulating levels of gonadotropins and T in 1000 h. Blood samples were obtained at 30, 60, 90, and 120 min; 3, 4, 6, healthy, eugonadal young men. 8, 12, and 24 h; and 2, 3, 4, and 7 d after injection. The initial two subjects received injections beginning with placebo, followed (during subse- quent admissions) by escalating doses of acyline at 2.5, 7.5, 25, and 75 Abbreviations: T, Testosterone. ␮g/kg. After determining that acyline caused minimal local effects and 3215 3216 J Clin Endocrinol Metab, July 2002, 87(7):3215–3220 Herbst et al. • Acyline, a New GnRH Antagonist no clinically systemic adverse effects in these first two subjects, the next least 12 h after injection of acyline for all doses (Fig. 1, E and three subjects were randomized until it was noted that the first subject’s F). T levels were suppressed even longer after injection of 75 gonadotropin and T levels remained suppressed longer than 7 d after the ␮ Ϯ 75 ␮g/kg dose. Subsequent injections in all subjects were nonrandom- g/kg acyline to 13.3 1.3% of baseline for 48 h, equal to the ized and in escalating dosage. In four of eight subjects, serum gonad- time LH remained suppressed at this dose (Fig. 1C). For all otropin and T levels remained suppressed for 7 d after the injection of doses, mean serum T levels returned to baseline by 168 h (7 75 ␮g/kg acyline, and these four subjects had serial blood samples d), except after injection of the 75 ␮g/kg dose of acyline, drawn until hormone levels returned to baseline. Screening laboratory when the mean T level remained significantly below baseline studies were repeated on d 7 after each injection. A nurse or physician ␮ closely monitored all subjects after each acyline or placebo injection. A for 7 d. Seven days after injection of 75 g/kg acyline, T levels physician examined all subjects at screening and on d 7 after injections. had returned to baseline in half of the subjects. In three of the All study procedures involving human subjects were approved by the four subjects whose serum T levels were persistently low 7 d institutional review board at University of Washington and were per- formed at University of Washington Clinical Research Center in accor- after acyline injection, T levels returned to baseline between dance with institutional guidelines. 14–22 d after injection. The fourth subject terminated the study after the d 7 sample was obtained. Measurements FSH, LH, and T levels were measured by immunofluorometric assay Serum acyline levels (Delfia, Wallac, Inc., Turku, Finland). Samples from a given individual were run in one assay. The sensitivities of the assay for FSH and LH were Acyline levels were determined in four subjects after in- 0.016 and 0.019 IU/liter, respectively. The intraassay coefficient of vari- jection of 75 ␮g/kg acyline, two in whom T levels returned ation was 2.9%, and the interassay coefficient of variation was 6.1% for a mid-range of pooled FSH values of 0.96 IU/liter. The intraassay co- to baseline by 7 d after injection of acyline and two in whom efficient of variation was 3.2%, and the interassay coefficient of variation T stayed suppressed below baseline levels beyond 7 d. Three was 12.5% for a mid range of pooled LH values of 1.2 IU/liter. The assay of these subjects received a dose of 25 ␮g/kg acyline 14 d sensitivity for T was 0.5 nmol/liter. The T intraassay coefficient of before injection of the 75 ␮g/kg dose. One individual was variation was 4.4%, and the T interassay coefficient of variation was 7.3% ␮ for a mean of mid-range pooled values of 11.4 nmol/liter. Subjects were naive to sc acyline injections before the 75 g/kg dose.
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